A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis.

Autor:	Werts AD; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Fulton WB; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ladd MR; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Saad-Eldin A; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Chen YX; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Kovler ML; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Jia H; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Banfield EC; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Buck RH; Abbott Nutrition, Columbus, Ohio., Goehring K; Abbott Nutrition, Columbus, Ohio., Prindle T Jr; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Wang S; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Zhou Q; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Lu P; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Yamaguchi Y; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Sodhi CP; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: csodhi@jhmi.edu., Hackam DJ; Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: Dhackam1@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2020; Vol. 9 (3), pp. 403-423. Date of Electronic Publication: 2019 Nov 19.
DOI:	10.1016/j.jcmgh.2019.11.002
Abstrakt:	Background & Aims: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. Methods: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. Results: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was up-regulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. Conclusions: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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